Abstract
Human immunodeficiency virus type 1 (HIV-1) associated neuropathy is the most common neurological complication of HIV-1, with debilitating pain affecting the quality of life. HIV-1 gp120 plays an important role in the pathogenesis of HIV neuropathy via direct neurotoxic effects or indirect pro-inflammatory responses. Studies have shown that gp120-induced release of mediators from Schwann cells induce CCR5-dependent DRG neurotoxicity, however, CCR5 antagonists failed to improve pain in HIV- infected individuals. Thus, there is an urgent need for a better understanding of neuropathic pain pathogenesis and developing effective therapeutic strategies. Because lysosomal exocytosis in Schwann cells is an indispensable process for regulating myelination and demyelination, we determined the extent to which gp120 affected lysosomal exocytosis in human Schwann cells. We demonstrated that gp120 promoted the movement of lysosomes toward plasma membranes, induced lysosomal exocytosis, and increased the release of ATP into the extracellular media. Mechanistically, we demonstrated lysosome de-acidification, and activation of P2X4 and VNUT to underlie gp120-induced lysosome exocytosis. Functionally, we demonstrated that gp120-induced lysosome exocytosis and release of ATP from Schwann cells leads to increases in intracellular calcium and generation of cytosolic reactive oxygen species in DRG neurons. Our results suggest that gp120-induced lysosome exocytosis and release of ATP from Schwann cells and DRG neurons contribute to the pathogenesis of HIV-1 associated neuropathy.
Highlights
Schwann cells are the most abundant glial cells in the peripheral nervous system, ensheathing all axons of peripheral nerves as either myelinating or non-myelinating cells
We demonstrated that gp120 induced the movement of lysosomes toward the cell periphery, increased lysosomal exocytosis, and enhanced release of ATP from Schwann cells, and that these processes were sensitive to P2X4 and vesicular nucleotide transporter (VNUT) inhibition
We demonstrated that human immunodeficiency virus type 1 (HIV-1) gp120 promoted the movement of lysosomes toward plasma membranes followed subsequently by lysosomal exocytosis and release of ATP; this process is achieved by gp120-induced activation of lysosome P2X4 via lysosome de-acidification and VNUT coupling
Summary
Schwann cells are the most abundant glial cells in the peripheral nervous system, ensheathing all axons of peripheral nerves as either myelinating or non-myelinating cells. In addition to its role as insulators of axons, Schwann cells are crucial for the proper function and maintenance of peripheral nerves by providing metabolic and/or trophic support (Beirowski et al, 2014; Feldman et al, 2017; Sasaki et al, 2018) and modulating responses to nerve injury (Jessen and Mirsky, 2016; Kim et al, 2018). Disrupting Schwann cell function can compromise glial–axon communication, nerve homeostasis, and lead to fiber loss, neurodegeneration, and pain. Cellular and molecular mechanisms underlying communication between Schwann cells and dorsal root ganglia (DRG) neurons remain to be investigated, Schwann cell dysfunction could play a key role in the pathogenesis of peripheral neuropathy, a highly complex and prevalent disease affecting 2.4% of the general population. The causes of peripheral neuropathy, which may be hereditary or iatrogenic from the toxicity of drugs given as part of antiretroviral or chemotherapy regiments, are often secondary to systemic illnesses including diabetes and infectious causes such as human immunodeficiency virus type 1 (HIV-1)
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